1. Field of the Invention
The present invention relates to methods and apparatus for dispensing volumes of liquids and, more particularly, to methods and apparatus for automating dispensing liquid volumes.
2. Description of the Related Art
There are numerous applications where dispensing small volumes of liquids is useful. As used herein, unless further specified, a small volume refers to a volume less than 10 microliters, and optionally less than 1 microliter. For example, U.S. Pat. No. 6,296,673, which is incorporated herein by reference, describes performing experiments where less than 1 microliter of liquid is dispensed in order to determine crystallization conditions for molecules, particularly for proteins.
Repeatably dispensing reagents or other fluids with precision and accuracy can be a difficult task, particularly as the volume of liquid delivered decreases, as viscosity increases, and when what is dispensed varies experiment to experiment. For example, as indicated in U.S. Pat. No. 6,296,673, the composition of the liquids dispensed may stay the same or may vary experiment to experiment. Meanwhile, the viscosities and other flow properties of the reagents being dispensed can vary reagent to reagent. These variances become more technically significant and challenging as the volume that is dispensed decreases.
Several commercial low volume liquid dispensers are available, including, for example: Beckman Colter Corporation, including the Biomek FX and the Multimek 96/384 models; Zymark Corporation, including the Rapid Plate® models 96/384 microplate pipetting work station and the Sciclone ALH (advanced liquid handler) work station; Packard Bioscience, including the Multiprobe II and EX models and Multiprobe II HT and EX models; Robbins Scientific, including the Hydra Microdispensers; and Gilson Corporation, including the 215 liquid handler work station. These systems are examples of industry standard robot liquid handling systems that have been used to automate many different kinds of experimental procedures.
The above mentioned systems typically include a dispensing mechanism that is moved relative to a platform that can hold wide variety of substrates for receiving liquid, including 96-well, 384-well, and 1536-well microliter plates, tubes, vials, glass lights, reservoirs, etc. For example, the dispensing equipment may include a dispensing head mounted on or in association with a programmable X, X-Y or X-Y-Z table or carriage. The motion of the table may be electronically coordinated with the operation of the dispensing mechanism so that the dispenser can be caused to dispense volumes of reagent or other fluid at any one of a number of locations defined by the position of the X and Y axes of the X-Y table. In operation, the X-Y table moves the dispensing head to a desired location and then stops while the dispenser is caused to dispense an amount of reagent onto a location of the substrate at the desired location. After each dispensing operation is completed, the X-Y table then moves to the next location and the process repeats for as many locations as are necessary to complete the pattern. In some instances, the X-Y table does not come to a stop but rather continuously moves as fluid is dispensed. It is noted that the X-Y table may also be used to move the substrate relative to the dispensing mechanism.
Many of the existing dispensing methods and equipment possess limitations regarding their precision, accuracy and durability. As the volume of liquid that needs to be delivered for experimental procedures decreases and the demand for throughput increases, a need will continue to exist for more effective dispensing technologies.
One application for dispensing small volumes of liquids that is particularly relevant to Applicants' research is the crystallization of molecules, and particularly biomolecules, such as proteins. Applicants perform a great many crystallization experiments on proteins in conjunction with its structural biology and drug discovery research. For example, in the last 12 months, Applicants have used dispensing technology to set up more than 3 million protein crystallization experiments. Integral to these experiments is the dispensing of liquids at volumes less than 1 microliter. By performing so many crystallization experiments, Applicants have realized certain functional, reliability and durability limitations with existing dispensing technology. The dispensing technology described herein seeks to remedy these limitations.